Schedule H

Oral

• Capsules: 25 mg, 50 mg, 100 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Focal Onset Seizures (Partial-Onset Seizures) with or without Secondary Generalisation

As monotherapy or adjunctive therapy in adults with focal epilepsy.

Parameter Recommendation

Starting dose 100 mg orally once daily

Titration Increase by 100 mg/day every 1–2 weeks based on seizure control and tolerability

Usual maintenance dose 200–400 mg once daily (may be given in two divided doses)

Maximum dose 600 mg/day

Clinical Notes:

• Once-daily dosing possible due to long half-life (approximately 60 hours)

• Slower titration (every 2 weeks) recommended in patients at risk for CNS adverse effects

• Take with or without food; swallow capsules whole

• Ensure adequate hydration throughout therapy to reduce nephrolithiasis risk

1. Generalised Tonic-Clonic Seizures — Adjunctive Therapy

For patients with inadequate control on first-line antiepileptics or when standard AEDs are not tolerated.

Parameter Recommendation

Starting dose 100 mg orally once daily

Titration Increase by 100 mg/day every 1–2 weeks

Usual maintenance dose 300–400 mg once daily or in two divided doses

Maximum dose 600 mg/day

Clinical Notes:

• Evidence less robust than for focal seizures

• Reserve for adjunctive use when first-line agents inadequate

• Broad-spectrum activity may benefit mixed seizure types

Secondary Indications – Adults (Off-label, if any)

Indication Dose Duration Notes

Lennox-Gastaut Syndrome (Adjunctive) 100–400 mg/day in divided doses; titrate cautiously Long-term OFF-LABEL; Specialist only (Epileptology); Evidence: Small RCTs and Indian specialist neurology practice

Essential Tremor Starting: 25 mg/day; Titrate to 100–200 mg/day Variable; assess response at 8–12 weeks OFF-LABEL; Specialist only; Limited evidence; Reserve for resistant cases when propranolol and primidone not tolerated

Migraine Prophylaxis Starting: 50 mg/day; Titrate to 100–200 mg/day Long-term OFF-LABEL; Specialist only; Limited data; May benefit overweight patients due to weight loss effect

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Focal Onset Seizures — Adjunctive Therapy in Children ≥6 Years

Parameter Recommendation

Starting dose 1 mg/kg/day orally once daily

Titration Increase by 1 mg/kg/day every 1–2 weeks based on response and tolerability

Usual maintenance dose 4–8 mg/kg/day (once daily or in two divided doses)

Maximum dose 12 mg/kg/day or 600 mg/day (whichever is lower)

Clinical Notes:

• Minimum age: 6 years

• Use only under paediatric neurologist supervision

• Monitor closely for oligohidrosis (decreased sweating) and hyperthermia, especially in hot weather

• Weight monitoring essential — significant anorexia and weight loss may occur

• Ensure adequate fluid intake to minimise kidney stone risk

Safety Monitoring:

• Temperature regulation (especially during febrile illness or high ambient temperature)

• Weight and growth parameters every 3 months

• Mood and behavioural changes

• Serum bicarbonate if prolonged therapy

Secondary Indications – Paediatrics (Off-label, if any)

Indication Dose Notes

Generalised Seizures in Refractory Epilepsy Syndromes (e.g., Lennox-Gastaut) 2–8 mg/kg/day once daily or in divided doses OFF-LABEL; Specialist only (Paediatric Epileptology); Reserve for refractory cases unresponsive to first-line agents

Infantile Spasms (Adjunctive) 2–8 mg/kg/day OFF-LABEL; Specialist only; Very limited evidence; Only in tertiary epilepsy centres

Not recommended below 6 years of age except under specialist supervision in tertiary centres with paediatric epilepsy expertise.

Note: Zonisamide has a long elimination half-life (approximately 60 hours) that is prolonged further in renal impairment.

• Known hypersensitivity to zonisamide or any excipient

• Known hypersensitivity to sulfonamides (cross-reactivity possible)

• Severe hepatic impairment

• History of severe cutaneous adverse reactions (SJS/TEN) with any antiepileptic drug

• Acute angle-closure glaucoma

• Severe metabolic acidosis (serum bicarbonate <17 mmol/L) unrelated to another cause

• History of nephrolithiasis or predisposition to kidney stones — encourage adequate hydration (≥2 L/day in adults)

• Pre-existing cognitive impairment or psychiatric disorders — may worsen; monitor mood and cognition

• Depression or history of suicidal ideation — screen and monitor as per AED class warning

• Anorexia or underweight patients — significant weight loss may occur; monitor nutritional status

• Impaired thermoregulation — particularly concerning in children; risk of oligohidrosis and hyperthermia

• Concurrent use of other carbonic anhydrase inhibitors (topiramate, acetazolamide) — additive metabolic acidosis and nephrolithiasis risk

• Patients at risk of metabolic acidosis (chronic respiratory conditions, ketogenic diet, severe diarrhoea)

• Avoid abrupt discontinuation — taper over at least 2 weeks to prevent rebound seizures

Parameter Details

Risk Category Limited human data; animal studies show teratogenicity

Recommendation Avoid unless no safer alternative; use only if benefit clearly outweighs risk

Known Risks Possible increased risk of congenital malformations; metabolic acidosis may affect fetal growth

Preferred Alternatives Levetiracetam, lamotrigine (better safety data in pregnancy; preferred in Indian obstetric-neurology practice)

When May Be Used Only when seizure control inadequate with safer alternatives; monotherapy at lowest effective dose; joint neurology and obstetrics management

Monitoring High-dose folic acid supplementation (5 mg/day) pre-conception and throughout first trimester; detailed anomaly scan at 18–20 weeks; fetal growth surveillance; maternal serum bicarbonate

Note: Encourage enrolment in pregnancy registries for antiepileptic drugs.

Parameter Details

Compatibility Generally not recommended; use only if benefit outweighs risk

Drug Levels in Milk Moderate; relative infant dose may exceed 10%

Preferred Alternatives Levetiracetam, lamotrigine (better established safety during breastfeeding)

Infant Monitoring If breastfeeding continues, monitor infant for sedation, poor feeding, irritability, and inadequate weight gain

Parameter Recommendation

Starting dose 50 mg orally once daily

Titration Slower titration — every 2–3 weeks; increase by 50 mg increments

Special Risks Increased risk of dizziness, ataxia, falls; cognitive impairment; reduced renal clearance prolongs half-life; higher susceptibility to metabolic acidosis and dehydration

Monitoring Renal function at baseline and periodically; hydration status; serum bicarbonate; cognitive function; fall risk assessment

Maximum dose Titrate cautiously; many elderly patients controlled at 200–300 mg/day

Interacting Drug Mechanism / Effect Recommendation

Carbamazepine CYP3A4 induction reduces zonisamide levels by ~40% May need higher zonisamide dose; monitor seizure control

Phenytoin CYP3A4 induction reduces zonisamide levels May need higher zonisamide dose; monitor seizure control

Phenobarbital / Primidone Enzyme induction reduces zonisamide levels May need dose adjustment; monitor efficacy

Valproate Inhibits zonisamide metabolism; increases zonisamide levels Monitor for zonisamide toxicity (sedation, ataxia); may need dose reduction

Topiramate / Acetazolamide (other carbonic anhydrase inhibitors) Additive carbonic anhydrase inhibition Significantly increased risk of metabolic acidosis and nephrolithiasis; avoid combination if possible; if essential, monitor serum bicarbonate and ensure aggressive hydration

Interacting Drug Mechanism / Effect Recommendation

Rifampicin Strong CYP3A4 inducer; reduces zonisamide levels Monitor seizure control; may need zonisamide dose increase

CNS depressants (benzodiazepines, opioids, alcohol) Additive sedation and psychomotor impairment Advise caution; monitor for excessive drowsiness; counsel regarding driving

Oral contraceptives No significant pharmacokinetic interaction with zonisamide alone; however, enzyme-inducing co-medications may affect efficacy Monitor for breakthrough bleeding if combined with enzyme inducers

Lithium Possible additive CNS effects Monitor for neurotoxicity

Metformin Both may contribute to metabolic acidosis Monitor serum bicarbonate in diabetic patients

Antihypertensives Possible additive hypotension; dehydration risk if diuretics used Monitor blood pressure and hydration

• Somnolence and fatigue

• Dizziness and ataxia

• Anorexia and weight loss

• Nausea and abdominal discomfort

• Headache

• Irritability and agitation

• Cognitive impairment (word-finding difficulty, concentration problems)

• Diplopia

• Insomnia

• Rash (non-serious)

Note: Many CNS adverse effects are dose-related and improve with slower titration.

Adverse Effect Clinical Action

Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) Discontinue immediately; hospitalisation; dermatology consultation; do not rechallenge

DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) Discontinue immediately; supportive care; specialist referral

Aplastic Anaemia / Agranulocytosis Rare; discontinue; haematology referral

Metabolic Acidosis (chronic, especially in children) Monitor serum bicarbonate; consider dose reduction or discontinuation; sodium bicarbonate supplementation if mild

Nephrolithiasis Encourage hydration; renal imaging if symptomatic; consider discontinuation if recurrent

Oligohidrosis / Hyperthermia (especially in children) Monitor temperature; avoid excessive heat exposure; discontinue if severe

Suicidal Ideation / Behaviour Monitor closely; psychiatric evaluation; consider discontinuation if severe

Acute Myopia and Secondary Angle-Closure Glaucoma Rare; discontinue immediately; ophthalmology referral

Status Epilepticus on Abrupt Withdrawal Never stop abruptly; taper over at least 2 weeks

First 3 months Serum bicarbonate monthly (especially in children or those on ketogenic diet); weight monitoring; CNS and mood assessment at each visit

Every 3–6 months Serum bicarbonate; renal function; weight and BMI; seizure frequency; adverse effects review

Annually CBC; LFTs; renal function; growth parameters in children

As indicated Serum ammonia (if co-administered with valproate); renal imaging if symptoms suggestive of nephrolithiasis

• Zonisep (Sun Pharma)

• Zonegran (Eisai — limited availability)

• Seizun (Intas)

• Zoniscan (Cipla)

• Zonicare (Torrent)

• Zonisamide (Generic versions from multiple manufacturers)

Note: FDC with clonazepam available but not recommended for routine chronic use.

• Not included in NLEM; pricing not NPPA-controlled

• Prices vary across brands

• Available in government hospitals at reduced cost in some states

• Long half-life (approximately 60 hours) allows once-daily dosing — excellent for patients where adherence is a concern

• Sulfonamide structure — ask about sulfa allergy history before prescribing; though cross-reactivity is uncommon, vigilance for rash is warranted

• Causes significant weight loss — can be advantageous in obese patients with epilepsy but problematic in underweight patients or those with eating disorders

• Children are particularly susceptible to oligohidrosis and hyperthermia — counsel parents about avoiding excessive heat exposure and monitoring for reduced sweating during physical activity or fever

• Avoid combining with topiramate — both are carbonic anhydrase inhibitors; combination significantly increases metabolic acidosis and nephrolithiasis risk

• Educate patients to report any rash immediately — while most rashes are benign, early recognition of SJS/TEN is critical

• Not first-line for generalised epilepsies — use as adjunctive therapy when first-line agents are ineffective or not tolerated

Zonisamide; antiepileptic; focal seizures; partial epilepsy; sulfonamide; sulfa-allergy caution; weight loss; metabolic acidosis; nephrolithiasis; oligohidrosis; SJS/TEN risk; renal-adjustment; paediatric-approved; Schedule H

RxIndia v1.0 — 01 May 2025

• CDSCO approved product information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• API Textbook of Medicine — Epilepsy chapter

• AIIMS Neurology Department Treatment Protocols

• IAP Guidelines for Paediatric Epilepsy Management

• Indian Epilepsy Society recommendations

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• Indian hospital neurology protocols (tertiary centres)